10-Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the folate metabolic pathway that contributes to DNA, protein and small molecule methylation. Previous studies have linked common genetic polymorphisms in the human MTHFR gene to a variety of human diseases, including homocysteinemia - a risk factor for cardiovascular disease. However, the full range of common genetic polymorphisms in the human MTHFR gene remains unclear. Furthermore, the underlying cellular mechanisms by which common nonsynonymous cSNPs might alter the function of this enzyme remain to be fully explored. This proposal focuses on the systematic identification and investigation of common functional polymorphisms in the MTHFR gene using a genotype-to-phenotype approach - followed by studies of their molecular mechanisms. This experimental strategy includes performing functional studies for all nonsynonymous cSNPs and common promoter haplotypes identified from gene resequencing, characterizing molecular mechanism(s) by which variant MTHFR sequences affect enzyme function, and characterizing the two MTHFR isoforms. This work has the potential to contribute significantly to our understanding of MTHFR functional genomics. [unreadable] [unreadable]